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Personalised human albumin in patients with cirrhosis and ascites: design and rationale for the ALB-TRIAL - a randomised clinical biomarker validation trial
Torp, N., Israelsen, M., Coenraad, M., Papp, M., Shawcross, D., Korenjak, M., Angeli, P., Laleman, W., Juanola, A., Gines, P., et al
BMJ open. 2024;14(2):e079309
Abstract
INTRODUCTION Human albumin is used in the treatment of complications of cirrhosis. However, the use of long-term human albumin administration is costly and resource demanding for both patients and healthcare systems. A precision medicine approach with biomarkers to predict human albumin treatment response, so-called predictive biomarkers, could make this a viable treatment option in patients with cirrhosis and ascites. METHODS AND ANALYSIS ALB-TRIAL is a multinational, double-blind, placebo-controlled randomised controlled trial. We aim to validate a predictive biomarker, consisting of a panel of circulating metabolites, to predict the treatment response to human albumin in patients with cirrhosis and ascites. All enrolled patients are stratified into a high-expected or low-expected effect stratum of human albumin based on the biomarker outcome. After stratification, patients in each group are randomised into either active treatment (20% human albumin) or corresponding placebo (0.9% NaCl) every 10th day for 6 months. The primary outcome is the cumulative number of liver-related events (composite of decompensation episodes, transjugular intrahepatic shunt insertion, liver transplantation and death). Key secondary outcomes include time-to-event analysis of primary outcome components, an analysis of the total healthcare burden and a health economic analysis. ETHICS AND DISSEMINATION The trial obtained ethical and regulatory approval in Denmark, Germany, the Netherlands, Belgium, Hungary and Spain through the Clinical Trials Information System (CTIS) from 13 February 2023, while UK approvals from the Health Regulatory Authority, Medicines and Healthcare products Regulatory Agency and Research Ethics Committee are pending. Findings will be published in peer-reviewed journals, presented at conferences, communicated to relevant stakeholders and in the public registry of CTIS, following trial completion. TRIAL REGISTRATION NUMBER NCT05056220 EU CT 2022-501006-34-01.
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Esophageal Stent in Acute Refractory Variceal Bleeding: A Systematic Review and a Meta-Analysis
Songtanin, B., Kahathuduwa, C., Nugent, K.
Journal of clinical medicine. 2024;13(2)
Abstract
Background: Acute esophageal variceal bleeding accounts for up to 70% of upper-gastrointestinal bleeding in cirrhotic patients. About 10-20% of patients with acute variceal bleeding have refractory bleeding that is not controlled by medical or endoscopic therapy, and this condition can be life-threatening. Balloon tamponade is a long-standing therapy which is only effective temporarily and has several complications, while transjugular intrahepatic portosystemic shunt (TIPS) and liver transplantation may not be readily available at some centers. The use of self-expandable metal stents (SEMSs) in refractory esophageal variceal bleeding has been studied for effectiveness and adverse events and has been recommended for use as a bridge to a more definitive treatment. Aim: To investigate the effectiveness and safety of SEMSs in managing refractory variceal bleeding. Methods: A systematic search of the MEDLINE, EMBASE, and Cochrane library databases was performed from inception to October 2022 using the following terms: "esophageal stent", "self-expandable metal stents", "endoscopic hemostasis", "refractory esophageal varices", and "esophageal variceal bleeding". Studies were included in the meta-analysis if they met the following criteria: (1) patients' age older than 18 and (2) a study (or case series) that has at least 10 patients in the study. Exclusion criteria included (1) non-English publications, (2) in case of overlapping cohorts, data from the most recent and/or most appropriate comprehensive report were collected. DerSimonian-Laird random-effects meta-analysis was performed using the meta package in R statistical software(version 4.2.2). Results: Twelve studies involving 225 patients with 228 stents were included in the analyses. The mean age and/or median age ranged from 49.4 to 69 years, with a male-to-female ratio of 4.4 to 1. The median follow-up period was 42 days. The mean SEMS dwell time was 9.4 days. The most common cause of acute refractory variceal bleeding in chronic liver disease patients included alcohol use followed by viral hepatitis. The pooled rate of immediate bleeding control was 91% (95% CI 82-95%, I(2) = 0). The pooled rate of rebleeding was 17% (95% CI 8-32%, I(2) = 69). The pooled rate of stent ulceration was 7% (95% CI 3-13%, I(2) = 0), and the pooled rate of stent migration was 18% (95% CI 9-32%, I(2) = 38). The pooled rate of all-cause mortality was 38% (95% CI 30-47%, I(2) = 34). Conclusions: SEMSs should be primarily considered as salvage therapy when endoscopic band ligation and sclerotherapy fail and can be used as a bridge to emergent TIPS or definitive therapy, such as liver transplantation.
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Terlipressin in combination with albumin as a therapy for hepatorenal syndrome in patients aged 65 years or older
Mujtaba, M. A., Gamilla-Crudo, A. K., Merwat, S. N., Hussain, S. A., Kueht, M., Karim, A., Khattak, M. W., Rooney, P. J., Jamil, K.
Annals of hepatology. 2023;28(5):101126
Abstract
INTRODUCTION AND OBJECTIVES Clinical data for older patients with advanced liver disease are limited. This post hoc analysis evaluated the efficacy and safety of terlipressin in patients aged ≥65 years with hepatorenal syndrome using data from 3 Phase III, randomized, placebo-controlled studies (OT-0401, REVERSE, CONFIRM). PATIENTS AND METHODS The pooled population of patients aged ≥65 years (terlipressin, n = 54; placebo, n = 36) was evaluated for hepatorenal syndrome reversal-defined as a serum creatinine level ≤1.5 mg/dL (≤132.6 μmol/L) while receiving terlipressin or placebo, without renal replacement therapy, liver transplantation, or death-and the incidence of renal replacement therapy (RRT). Safety analyses included an assessment of adverse events. RESULTS Hepatorenal syndrome reversal was almost 2-times higher in terlipressin-treated patients compared with patients who received placebo (31.5% vs 16.7%; P = 0.143). Among surviving patients, the need for RRT was significantly reduced in the terlipressin group, with an almost 3-times lower incidence of RRT versus the placebo group (Day 90: 25.0% vs 70.6%; P = 0.005). Among 23 liver-transplant-listed patients, significantly fewer patients in the terlipressin versus placebo group needed RRT by Days 30 and 60 (P = 0.027 each). Fewer patients in the terlipressin group needed RRT post-transplant (P = 0.011). More terlipressin-treated patients who were listed for and received a liver transplant were alive and RRT-free by Day 90. No new safety signals were revealed in the older subpopulation compared with previously published data. CONCLUSIONS Terlipressin therapy may lead to clinical improvements in highly vulnerable patients aged ≥65 years with hepatorenal syndrome. CLINICAL TRIAL NUMBERS OT-0401, NCT00089570; REVERSE, NCT01143246; CONFIRM, NCT02770716.
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Parenclitic network mapping identifies response to targeted albumin therapy in patients hospitalized with decompensated cirrhosis
Oyelade T, Forrest E, Moore KP, O'Brien A, Mani AR
Clinical and translational gastroenterology. 2023
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Abstract
BACKGROUND The efficacy of targeted albumin therapy in the management of decompensatory events in cirrhosis is unclear with different reports showing conflicting results. It is possible that only certain subgroups of patients may benefit from targeted albumin administration. However, extensive conventional subgroup analyses have not yet identified these subgroups. Albumin is an important regulator of physiological networks and may interact with homeostatic mechanism differently in patients according to the integrity of their physiological network. In the present study we aimed to assess the value of network mapping in predicting response to targeted albumin therapy in patients with cirrhosis. METHOD This is a sub-study of the ATTIRE trial; a multicentre, randomized trial conducted to assess the effect of targeted albumin therapy in cirrhosis. Baseline serum bilirubin, albumin, sodium, creatinine, CRP, and white cell count (WCC), international normalised ratio, heart rate, and blood pressure of 777 patients followed up for 6 months were used for network mapping using parenclitic analysis. Parenclitic network analysis involves measuring the deviation of each individual patient from the existing network of physiological interactions in a reference population. RESULT Overall network connectivity as well as deviations along WCC-CRP axis predicted 6-month survival independent of age and model for end-stage liver disease (MELD) in the standard care arm. Patients with lower deviation along the WCC-CRP axis showed lower survival in response to targeted albumin administration over 6-month follow-up period. Likewise, patients with higher overall physiological connectivity survived significantly less than the standard care group following targeted albumin infusion. CONCLUSION The parenclitic network mapping can predict survival of patients with cirrhosis and identify patient subgroups that don't benefit from targeted albumin therapy.
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Efficacy and Safety of Prothrombin Complex Concentrates in Liver Transplantation: Evidence from Observational Studies
Punzo, G., Di Franco, V., Perilli, V., Sacco, T., Sollazzi, L., Aceto, P.
Journal of clinical medicine. 2023;12(11)
Abstract
The risk/benefit ratio of using prothrombin complex concentrates (PCCs) to correct coagulation defects in patients with end-stage liver disease is still unclear. The primary aim of this review was to assess the clinical effectiveness of PCCs in reducing transfusion requirements in patients undergoing liver transplantation (LT). This systematic review of non-randomized clinical trials was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The protocol was previously registered (PROSPEROCRD42022357627). The primary outcome was the mean number of transfused units for each blood product, including red blood cells (RBCs), fresh frozen plasma, platelets, and cryoprecipitate. Secondary outcomes included the incidence of arterial thrombosis, acute kidney injury, and haemodialysis, and hospital and intensive care unit length of stay. There were 638 patients from 4 studies considered for meta-analysis. PCC use did not affect blood product transfusions. Sensitivity analysis, including only four-factor PCC, showed a significant reduction of RBC effect size (MD: 2.06; 95%CI: 1.27-2.84) with no true heterogeneity. No significant differences in secondary outcomes were detected. Preliminary evidence indicated a lack of PCC efficacy in reducing blood product transfusions during LT, but further investigation is needed. In particular, future studies should be tailored to establish if LT patients will likely benefit from four-factor PCC therapy.
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Continuous vs. intermittent terlipressin infusion for portal hypertension: a systematic review and meta-analysis
Hassan, M., Merza, N., Nawras, Y., Bahbah, E. I., Al-Hillan, A., Ahmed, Z., ElSheref, Sedm, Dahiya, D. S., Dar, S., Al Azzawi, M., et al
Annals of medicine and surgery (2012). 2023;85(10):5001-5010
Abstract
BACKGROUND Portal hypertension, a major complication of chronic liver disease, often leads to life-threatening variceal bleeding, managed effectively with vasoactive drugs like terlipressin. However, the most optimal method of terlipressin administration, continuous versus intermittent infusion, remains a subject of debate, necessitating this systematic review and meta-analysis for evidence-based decision-making in managing this critical condition. METHODS This systematic review and meta-analysis adhered to the PRISMA standards and explored multiple databases until 6 April 2023, such as MEDLINE through PubMed, Scopus, Web of Science, and CENTRAL. Independent reviewers selected randomized controlled trials (RCTs) that met specific inclusion criteria. After assessing study quality and extracting necessary data, statistical analysis was performed using Review Manager (RevMan), with results presented as risk ratios (RR) or mean differences. RESULTS Five RCTs (n=395 patients) were included. The continuous terlipressin group had a significantly lower risk of rebleeding (RR=0.43, P=0.0004) and treatment failure (RR=0.22, P=0.02) and fewer total adverse effects (RR=0.52, P<0.00001) compared to the intermittent group. However, there were no significant differences between the two groups in mean arterial pressure (P=0.26), length of hospital stays (P=0.78), and mortality rates (P=0.65). CONCLUSION This study provides robust evidence suggesting that continuous terlipressin infusion may be superior to intermittent infusions in reducing the risk of rebleeding, treatment failure, and adverse effects in patients with portal hypertension. However, further large-scale, high-quality RCTs are required to confirm these findings and to investigate the potential benefits of continuous terlipressin infusion on mortality and hospital stays.
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Lusutrombopag for thrombocytopenia in Chinese patients with chronic liver disease undergoing invasive procedures
Ding, Z., Wu, H., Zeng, Y., Kuang, M., Yang, W., Meng, Z., Chen, Y., Hao, C., Zou, S., Sun, H., et al
Hepatology International. 2023;17(1):180-189
Abstract
PURPOSE Probing efficacy and safety of lusutrombopag in Chinese chronic liver disease (CLD) and severe thrombocytopenia (PLT < 50 × 10(9)/L) patients undergoing elective invasive procedures. METHODS In this double-blind, parallel-group phase 3 study, 66 patients with CLD and severe thrombocytopenia were randomized 2:1 to lusutrombopag or placebo arm treatment regimens for seven days at 9 centers in China. Responders (PLT ≥ 50 × 10(9)/L that increased to ≥ 20 × 10(9)/L from the baseline and not received rescue therapy for bleeding) on Day 8 (the day after seven-day treatment) were assessed. PLT ≥ 50 × 10(9)/L on or after Day 8 and within 2 days before invasive procedure (alternative criteria for not requiring platelet transfusion) were also analyzed. Adverse events (AEs) were recorded. RESULTS The proportion of responders on Day 8 was evidently higher (p = 0.0011) in the lusutrombopag group (43.2%, 19/44) versus placebo (4.5%, 1/22). And 72.7% (32/44) patients receiving lusutrombopag met the alternative criteria for not requiring platelet transfusion, while 18.2% (4/22) in the placebo group. The median maximum PLT in lusutrombopag group increased to 80.5 × 10(9)/L, and median time to reach maximum was 14.5 days. Compared with placebo, the lusutrombopag group had a lower incidence of bleeding events (6.8% versus 13.6%), and only one patient had thrombotic-related AE. Overall, the incidence of treatment-emergent AEs was comparable between two groups. CONCLUSIONS Lusutrombopag was effective in raising PLT, diminishing platelet transfusion requirement, and documented a safety profile like the placebo in CLD and severe thrombocytopenia patients in a Chinese cohort undergoing elective invasive procedures. Chinese clinical trial registration number: CTR20192384.
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Comparative Efficacy of Early TIPS, Non-Early TIPS, and Standard treatment in patients with cirrhosis and acute variceal bleeding: a network meta-analysis
Huang, Y., Wang, X., Li, X., Sun, S., Xie, Y., Yin, X.
International journal of surgery (London, England). 2023
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Editor's Choice
Abstract
BACKGROUND Cirrhosis is a chronic disease characterized by chronic liver inflammation and diffuse fibrosis. A combination of vasoactive drugs, preventive antibiotics, and endoscopy is the recommended standard treatment for patients with acute variceal bleeding; however, this has been challenged. We compared the effects of early transjugular intrahepatic portosystemic shunt (TIPS), non-early TIPS, and standard treatment in patients with cirrhosis and acute variceal bleeding. MATERIALS AND METHODS The present network meta-analysis was conducted in accordance with the criteria outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Assessing the methodological quality of systematic reviews guidelines. The review has been registered with the International Prospective Register of Systematic Reviews. The PubMed, Embase, Cochrane Library, ClinicalTrials.gov, and World Health Organization-approved trial registry databases were searched for randomized controlled trials (RCTs) evaluating early TIPS, non-early TIPS, and standard treatment in patients with cirrhosis and acute variceal bleeding. RESULTS Twenty-four RCTs (1,894 patients) were included in the review. Compared with standard treatment, early TIPS (odds ratio [OR], 0.53; 95% credible interval [CrI], 0.30-0.94; surface under the cumulative ranking curve [SUCRA], 98.3) had a lower risk of all-cause mortality (moderate-to-high-quality evidence), and early TIPS (OR, 0.19; 95% CrI, 0.11-0.28; SUCRA, 98.2) and non-early TIPS (OR, 0.30, 95% CrI: 0.23-0.42; SUCRA, 1.8) were associated with a lower risk of rebleeding (moderate-to-high-quality evidence). Early TIPS was not associated with a reduced risk of hepatic encephalopathy, and non-early TIPS (OR, 2.78; 95% CrI, 1.89-4.23, SUCRA, 0) was associated with an increased incidence of hepatic encephalopathy (moderate-to-high-quality evidence). There was no difference in the incidence of new or worsening ascites (moderate-to-high-quality evidence) among the three interventions. CONCLUSION Based on the moderate-to-high quality evidence presented in this study, early TIPS placement was associated with reduced all-cause mortality [with a median follow-up of 1.9 years (25th-75th percentile range 1.9-2.3 years)] and rebleeding compared to standard treatment and non-early TIPS. Although early TIPS and standard treatment had a comparable incidence of hepatic encephalopathy, early TIPS showed superiority over non-early TIPS in this aspect. Recent studies have also shown promising results in controlling TIPS-related hepatic encephalopathy. However, it is important to consider individual patient characteristics and weigh the potential benefits against the risks associated with early TIPS. Therefore, we recommend that clinicians carefully evaluate the patient's condition, considering factors such as severity of variceal bleeding, underlying liver disease, and overall clinical status, before making a treatment decision. Further well-designed RCTs comparing early TIPS with non-early TIPS are needed to validate these findings and provide more definitive guidance.
PICO Summary
Population
Patients with cirrhosis and acute variceal bleeding (24 randomised controlled trials, n= 1,894).
Intervention
Early transjugular intrahepatic portosystemic shunt (TIPS).
Comparison
Non-early TIPS. Standard treatment.
Outcome
Compared with standard treatment, early TIPS (odds ratio (OR) 0.53; 95% credible interval (CrI), [0.30, 0.94]; surface under the cumulative ranking curve [SUCRA], 98.3) had a lower risk of all-cause mortality (moderate-to-high-quality evidence), and early TIPS (OR, 0.19; 95% CrI [0.11, 0.28]; SUCRA, 98.2) and non-early TIPS (OR, 0.30; 95% CrI [0.23, 0.42]; SUCRA, 1.8) were associated with a lower risk of rebleeding (moderate-to-high-quality evidence). Early TIPS was not associated with a reduced risk of hepatic encephalopathy, and non-early TIPS (OR 2.78; 95% CrI [1.89, 4.23] SUCRA, 0) was associated with an increased incidence of hepatic encephalopathy (moderate-to-high-quality evidence). There was no difference in the incidence of new or worsening ascites (moderate-to-high-quality evidence) among the three interventions.
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Comparison of clinical effect of octreotide and pituitrin in treatment of upper gastrointestinal hemorrhage in cirrhosis
Zhu Y, Ren Y, Li C, Si Z, Chi N
Indian journal of pharmacology. 2023;55(1):21-26
Abstract
OBJECTIVE The objective of the study was to compare and observe the therapeutic effect of octreotide and pituitrin in upper gastrointestinal hemorrhage caused by cirrhosis. MATERIALS AND METHODS In this prospective, randomized, open, single-blind, controlled, and single-center study, patients with upper gastrointestinal hemorrhage induced by cirrhosis were divided into control group (treated with pituitrin) and experimental group (treated with octreotide). The effective time, hemostasis time, and average bleeding volume of the two groups were observed and recorded, and the incidence of adverse reactions, rebleeding rate, and total effective rate of the two groups were compared. RESULTS One hundred and thirty-two patients with upper gastrointestinal hemorrhage caused by cirrhosis were included from March 2017 to September 2018. By a single-blind method, the patients were randomly divided into control group (n = 66) and experimental group (n = 66). Compared with the control group, the effective time and hemostasis time of the drug were significantly shorter in the experimental group, whereas the average bleeding volume of patients was lower (average P < 0.05). Compare with the control group, the total effective rate was higher in the experimental group, whereas the incidence of adverse reactions was lower (average P < 0.05). During 1-year follow-up, early and late rebleeding rates and hemorrhage-related mortality between the two groups have no difference (average P > 0.05). CONCLUSION In the treatment of upper gastrointestinal hemorrhage in cirrhosis, octreotide is superior to pituitrin, with advantages of quick onset, short hemostasis time, and less adverse reactions, which is helpful to control the rebleeding rate and bleeding-related mortality.
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Prophylactic fresh frozen plasma versus prothrombin complex concentrate for preprocedural management of the coagulopathy of liver disease: A systematic review
Evans CR, Cuker A, Crowther M, Pishko AM
Research and practice in thrombosis and haemostasis. 2022;6(4):e12724
Abstract
BACKGROUND The optimal prophylactic preprocedural management of patients with coagulopathy due to liver disease is not known. OBJECTIVES Our objective was to compare the efficacy and safety of fresh frozen plasma (FFP) with prothrombin complex concentrate (PCC) in the preprocedural management of patients with coagulopathy of liver disease. METHODS We conducted a systematic review to examine published evidence regarding treatment with FFP or PCC in adults with coagulopathy of liver disease undergoing an invasive procedure. Direct comparisons and single-arm studies were eligible. Efficacy outcomes included major bleeding, mortality, and correction of prothrombin time (PT) and/or international normalized ratio (INR). Safety outcomes included thrombosis and transfusion-related complications. RESULTS A total of 95 articles were identified for full-text review. Nine studies were eligible and included in the review. No randomized trials comparing FFP versus PCC were identified. Only two studies directly compared FFP versus PCC. In these studies, PCC appeared to result in higher rates of correction of PT/INR, but bleeding outcomes were not different. In the single-arm studies, bleeding events appeared low overall. Volume overload was the most common recorded adverse event in patients receiving FFP. Thromboembolic events occurred rarely, but exclusively in the PCC group. Due to heterogeneity in study definitions and bias, meta-analysis was not possible. Our study found no evidence to favor a specific product over another. CONCLUSIONS Insufficient data exist on the effects of FFP versus PCC administration before invasive procedures in patients with coagulopathy of liver disease to make conclusions with respect to relative efficacy or safety.